Pulmonary Delivery of Specialized Pro-Resolving Mediators-Based Nanotherapeutics Attenuates Pulmonary Fibrosis in Preclinical Animal Models

Pulmonary fibrosis (PF) is a chronic lung disease characterizedby excess extracellular matrix deposition and prolonged inflammationthat fails to resolve and is druggable. Using resolvins and theirprecursors for inflammation resolution, we demonstrate a nano-enabledapproach for accomplishing robust antifibrotic effects in bleomycin-or engineered nanomaterial-induced mouse and rat PF models. Targetingthe lipid peroxidation-triggered NLRP3 inflammasome and NF-& kappa;Bpathway in macrophages and the ROS-mediated TGF-& beta;/Smad and S1Psignaling in epithelial cells results in these potent protective effectsat the ng/mL dosimetry. We further develop an inhalable biocompatiblenanoparticle that encapsulates fish oil, a chosen resolvin precursor,with phosphatidylcholine and polyethylene glycol to enhance drug permeabilityand facilitate crossing the mucosal barrier, forming fish-oilsome (FOS). Oropharyngeal aspiration andinhalation of FOS improved the anti-inflammatory status, histologicalcharacteristics, and pulmonary function in fibrotic lungs, which wasmechanistically supported by transcriptomic and proteomic analyses.Further, scale-up engineered FOS samples with the desired physicochemicalproperties, anti-PF efficacy, and in vivo biocompatibilitywere validated in different batch sizes (up to 0.2 L/batch). Thisstudy provides a practical and translatable approach to promotinginflammation resolution and PF treatment.

Automated summary

Researchers have developed a nano-enabled approach using resolvins and their precursors to effectively treat pulmonary fibrosis in mouse and rat models. They have also created an inhalable nanoparticle called fish-oilsome (FOS) that encapsulates fish oil and enhances drug permeability. Inhalation of FOS has shown improvements in inflammation status, histological characteristics, and pulmonary function in fibrotic lungs, supported by transcriptomic and proteomic analyses.